The overall goal of the University of Texas MD Anderson Cancer Center (MDACC) Ovarian Cancer SPORE is to improve outcomes for ovarian cancer patients by combining targeted agents based upon the molecular, cellular and clinical biology of their disease and understanding and targeting mechanisms of drug resistance. Over the last 6 years (FY2009-FY2015), MDACC has cared for 4,483 patients with ovarian, fallopian tube and peritoneal cancers. MDACC has given high priority to ovarian cancer research through recruitment, salary support, clinical facilities, laboratory space, and philanthropic funds. Over the last 6 years, MDACC has recruited six outstanding faculty members with an interest in ovarian cancer research (Drs. Amir Jazaeri, Larissa Meyer, Alpa Nick, Shannon Westin, Melinda Yates, and Behrouz Zand). Philanthropic support of the Women?s Cancer Breast-Ovarian Moon Shot has provided organization and infrastructure. Over the same time period, our previous SPORE funded 15 Developmental Research Projects (DRPs), and supported six Career Enhancement Program (CEP) awardees, and SPORE investigators have contributed 461 peer-reviewed papers pertaining to ovarian cancer with 53% (246) IF >5 and 20% (92) >10. Achievements included: 1) evaluation of a two stage screening strategy with a positive predictive value of >30% for detecting stage I-II disease in 9 of 12 cases detected; 2) identification of biomarkers that detect 18% of CA125 negative cases; 3) development of a point-of-service nanoassay for these biomarkers; 4) discovery that anti-TP53 autoantibodies rise 5 (median) -13 months (mean) prior to CA125, the first biomarker to provide earlier detection than CA125; 4) observation of a 54% objective response rate to anti-angiogenic therapy with aflibercept and docetaxel; 5) initiation of a trial targeting Dll4 and notch; 6 ) CSF1R inhibitors could deplete macrophages and reduce resistance to anti-VEGF Therapy 7) demonstration of significant activity of the MEK inhibitor selumetinib in low-grade ovarian cancers and initiation of an international phase III trial of another potent MEK inhibitor trametinib; 8) development of a robust biomarker panel that predicts response to PARP inhibitors (PARPi) and initiation of multiple trials combining PI3K and PARP inhibitors in high-grade ovarian cancer; and 9) use of mesenchymal stem cells to deliver interferon to ovarian cancers. I n t h i s new SPORE application, 4 projects will strive to: 1) validate predictive biomarkers and implement rational combination therapy with PARP inhibitors designed to overcome pre- existing and adaptive resistance; 2) validate predictive biomarkers and implement rational combination therapy with MEK inhibitor for low-grade ovarian serous cancers to overcome resistance; 3) target macrophages to overcome resistance to anti-VEGF therapies; and 4) evaluate a novel SIK2 inhibitor in a Phase IA/B trial and identify agents that produce synthetic lethality.
Overall NARRATIVE The SPORE will improve outcomes for ovarian cancer patients by combining agents that target high-grade and low-grade ovarian cancer cells, tumor-associated blood vessels and an enzyme (SIK2) required for cancer cell division and survival, based on the abnormalities in each cancer.
|Gharpure, Kshipra M; Pradeep, Sunila; Sans, Marta et al. (2018) FABP4 as a key determinant of metastatic potential of ovarian cancer. Nat Commun 9:2923|
|Zhang, Lin; Peng, Dan; Sood, Anil K et al. (2018) Shedding Light on the Dark Cancer Genomes: Long Noncoding RNAs as Novel Biomarkers and Potential Therapeutic Targets for Cancer. Mol Cancer Ther 17:1816-1823|
|Hsieh, Hui-Ju; Zhang, Wei; Lin, Shu-Hong et al. (2018) Systems biology approach reveals a link between mTORC1 and G2/M DNA damage checkpoint recovery. Nat Commun 9:3982|
|Villar-Prados, Alejandro; Wu, Sherry Y; Court, Karem A et al. (2018) Predicting novel therapies and targets: Regulation of Notch3 by the bromodomain protein BRD4. Mol Cancer Ther :|
|Fleming, Nicole D; Nick, Alpa M; Coleman, Robert L et al. (2018) Laparoscopic Surgical Algorithm to Triage the Timing of Tumor Reductive Surgery in Advanced Ovarian Cancer. Obstet Gynecol 132:545-554|
|Allen, Julie K; Armaiz-Pena, Guillermo N; Nagaraja, Archana S et al. (2018) Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction. Cancer Res 78:3233-3242|
|Chen, Xiuhui; Mangala, Lingegowda S; Rodriguez-Aguayo, Cristian et al. (2018) RNA interference-based therapy and its delivery systems. Cancer Metastasis Rev 37:107-124|
|Umamaheswaran, Sujanitha; Dasari, Santosh K; Yang, Peiying et al. (2018) Stress, inflammation, and eicosanoids: an emerging perspective. Cancer Metastasis Rev 37:203-211|
|Zheng, Yiyan; Sethi, Ritika; Mangala, Lingegowda S et al. (2018) Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation. Nat Commun 9:476|
|Berger, Ashton C; Korkut, Anil; Kanchi, Rupa S et al. (2018) A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. Cancer Cell 33:690-705.e9|
Showing the most recent 10 out of 25 publications